1. Field of the Invention
The present invention relates generally to the fields of peptide chemistry and molecular pathology and more specifically to novel melanocortin receptor ligands.
2. Background Information
The melanocortin (MC) receptors are a group of cell surface proteins that mediate a variety of physiological effects, including regulation of adrenal gland function such as production of the glucocorticoid cortisol and aldosterone; control of melanocyte growth and pigment production; thermoregulation; immunomodulation; and analgesia. Five distinct MC receptors have been cloned and are expressed in a variety of tissues, including melanocytes, adrenal cortex, brain, gut, placenta, skeletal muscle, lung, spleen, thymus, bone marrow, pituitary, gonads and adipose tissue (Tatro, Neuroimmunomodulation 3:259-284 (1996)). Three MC receptors, MC1, MC3 and MC4, are expressed in brain tissue (Xia et al., Neuroreport 6:2193-2196 (1995)).
A variety of ligands termed melanocortins function as agonists that stimulate the activity of MC receptors. The melanocortins include melanocyte-stimulating hormones (MSH) such as xcex1-MSH, xcex2-MSH and xcex3-MSH, as well as adrenocorticotropic hormone (ACTH). Individual ligands can bind to multiple MC receptors with differing relative affinities. The variety of ligands and MC receptors with differential tissue-specific expression likely provides the molecular basis for the diverse physiological effects of melanocortins and MC receptors.
A particularly potent MC receptor ligand is an xcex1-MSH analogue, NDP. NDP has been used extensively to characterize MC receptors because it is chemically and enzymatically stable and binds with high affinity to all identified MC receptors. Despite the availability of NDP, no binding assay has been reported for the detection of MC receptors in brain tissue even though MC receptor messenger RNA is expressed in brain. Detection of MC receptors in brain is of particular interest since brain MC receptors mediate some of the physiological effects of melanocortins, including the antipyretic effect observed with experimentally induced fever.
Due to the varied physiological activities of MC receptors, high affinity ligands of MC receptors would be valuable to analyze the presence of MC receptors in particular cells or tissues. In addition, high affinity ligands of MC receptors could be used to exploit the varied physiological responses of MC receptors by functioning as potential therapeutic agents or as lead compounds for the development of therapeutic agents.
Thus, there exists a need for ligands that bind to MC receptors with high affinity and methods for detecting the presence of MC receptors in a cell or tissue such as brain. The present invention satisfies this need and provides related advantages as well.
The invention provides ligands for melanocortin (MC) receptors. For example, the invention provides the MC receptor peptide ligand Ac-Nle-Gln-His-(p(I)-D-Phe)-Arg-(D-Trp)-Gly-N2, (SEQ ID NO:1), where the iodo group is unlabeled or radioactively labeled. The invention additionally provides methods of assaying for MC receptors in a cell or tissue such as brain. The invention also relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a melanocortin receptor ligand and to methods of administering the pharmaceutical composition to a subject. The invention further provides tetrapeptide ligands for MC receptors and methods of altering MC receptor activity.